Abstract
We hypothesized that some molecular pathways might interact to initiate the process of nervous tissue destruction, promoting cardiac autonomic neuropathy (CAN) in the course of diabetes type 1 (T1D). The study group consisted of 60 T1D patients (58.33% women/41.67% men), on standard therapy. The control group consisted of twenty healthy volunteers recruited in accordance with age, gender and body weight. The presence of CAN was documented by the Ewing test method (ProSciCard apparatus). A microarray data analysis was performed using Gene Spring version 13. The microarray results for selected genes were confirmed by real-time PCR (qRT-PCR), using specific TaqMan Gene Expression Assays. Plasma IL‐6 content was measured by an enzyme-linked immunosorbent assay (ELISA). The p < 0.05 value was considered as statistically significant. The microarray analysis, confirmed by qRTPCR, showed significant up-regulation of autophagy, quantity of mitochondria, quality regulatory genes (mTOR, GABARAPL2) apoptosis, ER-stress and inflammation (NFKB1, IL1b, IL1R1, SOD1), in T1D when compared to the control group. A significantly higher IL-6 protein level was observed in T1D patients, in comparison to the control group. We concluded that the observed changes in gene expression and activation of intracellular pathways give a coherent picture of the important role of oxidative stress in inflammation and the activation of apoptosis in the pathomechanism of DM. The significance of the inflammatory process, confirmed by the increased level of the inflammation biomarker IL-6 in the pathomechanisms of CAN was shown even in patients with properly treated T1D.
Highlights
We hypothesized that some molecular pathways might interact to initiate the process of nervous tissue destruction, promoting cardiac autonomic neuropathy (CAN) in the course of diabetes type 1 (T1D)
The presented work is one of the first related to this field publications focusing on pathways involved in CAN development in T1D patients, undertaken by analysing blood cell gene expression measured by microarray
The analysis of gene expression in the investigated group of T1D patients documented the up-regulation of genes related to endoplasmic reticulum (ER)-stress
Summary
We hypothesized that some molecular pathways might interact to initiate the process of nervous tissue destruction, promoting cardiac autonomic neuropathy (CAN) in the course of diabetes type 1 (T1D). The microarray analysis, confirmed by qRTPCR, showed significant up-regulation of autophagy, quantity of mitochondria, quality regulatory genes (mTOR, GABARAPL2) apoptosis, ER-stress and inflammation (NFKB1, IL1b, IL1R1, SOD1), in T1D when compared to the control group. The genetic risk of T1D has only recently been analysed using genome-wide association studies, identifying over 60 T1D related susceptibility regions within the human genome, marked by single nucleotide polymorphisms[2] This gene expression analysis revealed changes in genes related to inflammation (cytokines) and endoplasmic reticulum (ER) stress, leading to the activation of apoptosis[3]. The non-enzymatic glycation of proteins (AGEs) alter intracellular signalling through proinflammatory cytokines such as IL-6, TNF-α and free radicals, which further propagate diabetic complications[10]. This study’s goal is to follow, by microarray, the possible alteration of blood cell molecular pathways which may be altered to initiate the process of nervous tissue destruction in the course of T1D
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